Search Results (982)

Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master transcriptional regulator of cellular antioxidant responses through orchestration of cytoprotective gene expression, establishing its significance as a therapeutic target in cerebral pathophysiology. Classical electrophilic NRF2 activators, despite potent activation potential, exhibit paradoxically reduced therapeutic efficacy relative to single antioxidants, attributable to concurrent oxidative stress generation, glutathione depletion, mitochondrial impairment, and systemic toxicity. Although emerging non-electrophilic pharmacological activators offer therapeutic potential, their utility remains limited by bioavailability and suboptimal potency, underscoring the imperative for innovative therapeutic strategies to harness this cytoprotective pathway. Non-pharmacological interventions, including neuromodulation, physical exercise, and lifestyle modifications, activate NRF2 through non-canonical, non-electrophilic pathways involving protein–protein interaction inhibition, KEAP1 degradation, post-translational and transcriptional modulation, and protein stabilization, though mechanistic characterization remains incomplete. Such interventions utilize multi-mechanistic approaches that synergistically integrate multiple non-electrophilic NRF2 pathways or judiciously combine electrophilic and non-electrophilic mechanisms while mitigating electrophile-induced toxicity. This strategy confers neuroprotective effects without the contraindications characteristic of classical electrophilic activators. This review comprehensively examines the mechanistic underpinnings of non-pharmacological NRF2 modulation, highlighting non-electrophilic activation pathways that bypass the limitations inherent to electrophilic activators. The evidence presented herein positions non-pharmacological interventions as viable therapeutic approaches for achieving non-electrophilic NRF2 activation in the treatment of cerebrovascular and neurodegenerative pathologies. Full article

In this perspective article, we introduce Ecocebo as a novel concept describing the modulatory effects of physical environments, whether natural or built, on drug effect. Positioned as a spatial component of the placebo effect, Ecocebo is grounded in evidence-based design principles and proposes that environmental features such as natural light, greenery, spatial geometry, and calming esthetics can significantly influence sensory, emotional, and cognitive processes. These environmental factors may enhance or modify pharmacological responses, especially for analgesics, anxiolytics, and antidepressants. We highlighted how exposure to restorative spaces can reduce pain perception, stress, and the need for medication, paralleling findings in placebo research where contextual and sensory cues influence brain regions linked to emotion and pain regulation. We propose virtual reality (VR) as the most suitable methodological tool to study Ecocebo in controlled and ecologically valid settings. VR allows for the precise manipulation of spatial features and real-time monitoring of physiological and psychological responses. We also propose integrating VR with neuromodulation techniques to investigate brain–environment–drug interactions. Finally, we addressed key methodological challenges such as defining control conditions and standardizing the measurement of presence. This perspective opens new directions for the integration of non-pharmacological and pharmacological interventions and personalized therapeutic environments to optimize clinical outcomes. Full article

Chronic pain management is constantly evolving, and our literature review aims to describe the general innovations happening within the field. The need for advancements in chronic pain is a necessity, as debilitating back pain and other forms of chronic pain are significant issues in the United States. Traditionally, medications have been the initial treatment options in cases of chronic pain; however, the advancement in pharmacogenetics has led to an increased ability to create more personalized medication plans. Additionally, neuromodulation in spinal cord stimulation, transcranial magnetic stimulation, transcranial direct-current stimulation, and dorsal root ganglion stimulation continue to see increased usage in mainstream chronic pain management. These techniques have continued to prove successful in many chronic pain management cases. They are allowing practicing physicians more confidence in the variety of treatment options. Lastly, great strides have also been made in stem cell and regenerative therapies, such as platelet-rich plasma injections, and artificial intelligence, further advancing the various treatment options and overall efficiency of pain management. This review aims to critically analyze and review the most up-to-date literature within each section mentioned and comprehensively discuss the future of innovation in chronic pain management. Full article

Chronic pain is a dynamic, brain-wide condition that eludes effective management by conventional, static treatment approaches. Transcutaneous Electrical Nerve Stimulation (TENS), traditionally perceived as a simple and generic modality, is on the verge of a significant transformation. Guided by advances in brain-state decoding and adaptive algorithms, TENS can evolve into a precision neuromodulation system tailored to individual needs. By integrating multimodal neuroimaging—including the spatial resolution of functional magnetic resonance imaging (fMRI), the temporal sensitivity of an Electroencephalogram (EEG), and the ecological validity of functional near-infrared spectroscopy (fNIRS)—with real-time machine learning, we envision a paradigm shift from fixed stimulation protocols to personalized, closed-loop modulation. This comprehensive review outlines a translational framework to reengineer TENS from an open-loop device into a responsive, intelligent therapeutic platform. We examine the underlying neurophysiological mechanisms, artificial intelligence (AI)-driven infrastructures, and ethical considerations essential for implementing this vision in clinical practice—not only for chronic pain management but also for broader neuroadaptive healthcare applications. Full article

Background: Emotion regulation (ER) plays a vital role in mental health, spanning mood, anxiety, and personality disorders. Cognitive reappraisal (CR) is one of the most common ER strategies and depends on prefrontal brain areas, but its success varies, and its neural basis is not fully clear. Interest is growing in using transcranial direct current stimulation (tDCS) to support ER, yet most studies have focused only on the dorsolateral prefrontal cortex (dlPFC) and used simple tasks. Objective: This study explored whether tDCS applied to either the dlPFC or the ventromedial prefrontal cortex (vmPFC) could shape autonomic responses during CR while people watched emotionally engaging film clips. Methods: Participants were randomly assigned to receive either active or sham tDCS over the dlPFC or vmPFC. While stimulated, they used CR strategies (positive reappraisal, fictional reappraisal, or distancing) to manage their reactions to negative film scenes. Heart rate (HR), skin conductance (SC), and respiratory rate (RR) were tracked throughout as physiological indicators. Results: Active dlPFC tDCS combined with CR led to significantly greater reductions in HR toward the end of emotional exposure, compared to sham or non-CR conditions. dlPFC stimulation also lowered HR even without explicit CR, pointing to possible effects on automatic regulation. vmPFC effects were inconsistent, and no reliable effects were observed for SC or RR. Conclusions: These results suggest that tDCS effects on autonomic ER depend on the brain region and timing. dlPFC stimulation may strengthen both intentional and automatic emotion regulation, especially when combined with reappraisal, highlighting the value of realistic emotional tasks in neuromodulation studies. Full article

Brain tumors elicit complex neuropsychiatric disturbances that frequently occur prior to radiological detection and hinder differentiation from major psychiatric disorders. These syndromes stem from tumor-dependent metabolic reprogramming, neuroimmune activation, neurotransmitter dysregulation, and large-scale circuit disruption. Dinucleotide hypermethylation (e.g., IDH-mutant gliomas), through the accumulation of 2-hydroxyglutarate (2-HG), execute broad DNA and histone hypermethylation, hypermethylating serotonergic and glutamatergic pathways, and contributing to a treatment-resistant cognitive-affective syndrome. High-grade gliomas promote glutamate excitotoxicity via system Xc⁻ transporter upregulation that contributes to cognitive and affective instability. Cytokine cascades induced by tumors (e.g., IL-6, TNF-α, IFN-γ) lead to the breakdown of the blood–brain barrier (BBB), which is thought to amplify neuroinflammatory processes similar to those seen in schizophrenia spectrum disorders and autoimmune encephalopathies. Frontal gliomas present with apathy and disinhibition, and temporal tumors lead to hallucinations, emotional lability, and episodic memory dysfunction. Tumor-associated neuropsychiatric dysfunction, despite increasing recognition, is underdiagnosed and commonly misdiagnosed. This paper seeks to consolidate the mechanistic understanding of these syndromes, drawing on perspectives from neuroimaging, molecular oncology, neuroimmunology, and computational psychiatry. Novel approaches, including lesion-network mapping, exosomal biomarkers or AI-based predictive modeling, have projected early detection and precision-targeted interventions. In the context of the limitations of conventional psychotropic treatments, mechanistically informed therapies, including neuromodulation, neuroimmune-based interventions, and metabolic reprogramming, are essential to improving psychiatric and oncological outcomes. Paraneoplastic neuropsychiatric syndromes are not due to a secondary effect, rather, they are manifestations integral to the biology of a tumor, so they require a new paradigm in both diagnosis and treatment. And defining their molecular and circuit-level underpinnings will propel the next frontier of precision psychiatry in neuro-oncology, cementing the understanding that psychiatric dysfunction is a core influencer of survival, resilience, and quality of life. Full article

Syzygium oleosum (F.Muell.) B.Hyland is an Australian native species whose essential oil (EO), known commercially as “Mango Myrtle,” is gaining popularity in aromatherapy, yet remains poorly studied. This work provides the first comprehensive pharmacognostic investigation of S. oleosum. Anatomical and micromorphological analyses revealed numerous secretory cavities and calcium oxalate druses in both leaves and twigs. GC-MS analysis identified 16 components in the EO, predominantly hydrocarbon monoterpenes, with terpinolene (30.79%), β-pinene (26.79%), α-pinene (10.69%), and γ-terpinene (9.86%) as major constituents. In vitro assays showed moderate antioxidants (IC₅₀ ≤ 4.95 mg/mL) and anti-inflammatory effects (IC₅₀ ≤ 5.93 mg/mL), with specific monoterpenes contributing differentially to each activity. The EO displayed weak inhibitory activity against acetylcholinesterase (IC₅₀ 19.4 mg/mL) and butyrylcholinesterase (IC₅₀ 15.9 mg/mL), and no effect on GABA transaminase. Microelectrode array recordings on primary cortical neurons demonstrated a concentration-dependent inhibition of network activity (0.059–1.19 mg/mL) without affecting cell viability, indicating a neuromodulatory property. These results provide new insights into the pharmacological potential of S. oleosum EO and support its further evaluation as a neuroactive and anti-inflammatory agent. Full article

Background: Peripheral nerve stimulation (PNS) has been employed as a therapeutic modality for managing chronic pain across diverse etiologies and neural targets. Nevertheless, its application in treating chronic axial neck pain remains markedly underexplored. Accordingly, this study aimed to both review the existing literature and present a retrospective single-center case series of patients who underwent temporary PNS targeting the cervical medial branch nerves (CMBNs) for chronic axial neck pain. Methods: This investigation comprises a narrative literature review alongside a single-center, retrospective case series evaluating percutaneous, temporary PNS for the management of cervical spondylosis facet arthropathy in the absence of myelopathy or radiculopathy. The primary outcomes were pain reduction, as measured by the numeric rating scale, and improvements in functional disability, with assessments conducted at baseline and at 60 days post-intervention. Results: PNS represents a neuromodulatory, nondestructive intervention that targets the CMBN to alleviate chronic axial neck pain, in contrast to the destructive mechanisms inherent in cervical radiofrequency ablation (CRFA). Although PNS has been applied to other neural targets, its use in the cervical region is sparsely documented, with limited case studies available. Notably, this case series is the first to report pain and disability outcomes specifically associated with CMBN PNS. At the 60-day follow-up, 66% of subjects achieved the minimal clinically important difference (MCID) for pain reduction, while 77% met the MCID for disability reduction. Moreover, our analysis uniquely examined the impact of previous CRFA and a history of cervical spine surgery on treatment outcomes, revealing that patients with such interventions experienced more modest improvements compared to their surgery- and CRFA-naive counterparts. Conclusions: The current literature reveals a significant gap regarding the use of CMBN PNS, underscoring an unmet need in the treatment algorithm for chronic axial neck pain beyond conservative modalities. Our findings suggest that CMBN PNS may offer a promising adjunctive therapy for carefully selected patients with refractory chronic axial neck pain who have not improved after medications, physical therapy, or injections. Additionally, the comparative analysis of outcomes in patients with a history of CRFA or cervical surgery underscores potential advantages of PNS prior to destructive therapies. Future research, ideally in the form of prospective studies with larger cohorts and extended follow-up durations, is warranted to further evaluate long-term outcomes and refine the place of PNS in the treatment algorithm. Full article

Background: Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Gamma (γ) oscillations are closely linked to learning and memory, and recent interest has grown around Gamma ENtrainment Using Sensory stimulation (GENUS) as a non-invasive neuromodulation strategy. However, the therapeutic impact of vibrotactile gamma stimulation under varying physical parameters such as acceleration remains underexplored. Methods: Differentiated SH-SY5Y cells were treated with amyloid-β (Aβ) and exposed to vibrotactile stimulation at 2.2 or 4.0 m/s². In vivo, male C57BL/6N mice (7 weeks old, 35 g) were administered scopolamine to induce neurotoxicity and randomly assigned to sham, scopolamine, donepezil, or vibrotactile stimulation groups (n = 10 each). Behavioral tests, biochemical assays, Western blotting, and immunohistochemistry were performed to evaluate cognitive function, oxidative stress, cholinergic activity, synaptic plasticity, and neuroinflammation. Results: In vitro, SH-SY5Y cells exposed to amyloid-beta (Aβ) were treated with vibrotactile stimulation, resulting in enhanced neuronal marker expression at 2.2 m/s². In vivo, mice receiving stimulation at 2.2 m/s² showed improved cognitive performance, reduced oxidative stress, restored cholinergic function, suppressed neuroinflammation, and enhanced synaptic plasticity. Mechanistically, these effects were associated with activation of the AKT/GSK3β/β-catenin pathway. Conclusions: Our findings demonstrate that vibrotactile gamma stimulation at 2.2 m/s² exerts greater therapeutic efficacy than higher acceleration, highlighting the importance of optimizing stimulation parameters. This work supports the potential of acceleration-tuned, non-invasive GENUS-based therapies as effective strategies for cognitive recovery in neurodegenerative conditions. Full article

Spatial navigation involves the use of external (allocentric) and internal (egocentric) processing. These processes interact differentially depending on age. In order to explore the effectiveness of these interactions in different age groups (study 1), we compared the performance of children and adults in a two-session spatial maze task. This task was performed under deprived vision, thus preventing visual cues critical for allocentric processing. Number of correct performances and performance time were recorded as outcome measures. We recruited thirty healthy participants for the children (mean age 10.97 ± 0.55) and the adult (mean age 21.16 ± 1.76) groups, respectively. The results revealed a significantly higher number of correct actions and shorter performance times during maze solving in children compared to adults. These differences between children and adults might be due to developmental and cortical reorganization factors influencing egocentric processing. Assuming that activation of the posterior parietal cortex (PPC) facilitates egocentric spatial processing, we applied excitatory anodal tDCS over the right PPC in a second study with a different healthy adult group (N = 30, mean age 21.23 ± 2.01). Using the same spatial navigation task as in study 1, we evaluated possible performance improvements in adults associated with this neuromodulation method. Compared to a sham stimulation group, anodal tDCS over the right PPC did not significantly improve spatial task performance. Full article

Heart failure, a significant global health burden, is divided into heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF), characterized by systolic dysfunction and diastolic stiffness, respectively. While HFrEF benefits from pharmacological and device-based therapies, HFpEF lacks effective treatments, with both conditions leading to high rehospitalization rates and reduced quality of life, especially in older adults with comorbidities. This review explores the role of artificial intelligence (AI) in advancing autonomic neuromodulation for heart failure management. AI enhances patient selection, optimizes stimulation strategies, and enables adaptive, closed-loop systems. In HFrEF, vagus nerve stimulation and baroreflex activation therapy improve functional status and biomarkers, while AI-driven models adjust stimulation dynamically based on physiological feedback. In HFpEF, AI aids in deep phenotyping to identify responsive subgroups for neuromodulatory interventions. Clinical tools support remote monitoring, risk assessment, and symptom detection. However, challenges like data integration, ethical oversight, and clinical adoption limit real-world application. Algorithm transparency, bias minimization, and equitable access are critical for success. Interdisciplinary collaboration and ethical innovation are essential to develop personalized, data-driven, patient-centered heart failure treatment strategies through AI-guided neuromodulation. Full article

A wearable closed-loop transcutaneous electrical nerve stimulation (TENS) platform has been developed to address the limitations of conventional open-loop neuromodulation systems. Unlike existing systems such as CLoSES—which targets intracranial stimulation—and electromyography-triggered functional electrical stimulation (EMG-FES) platforms primarily used for motor rehabilitation, the proposed device uniquely integrates low-latency surface electromyography (sEMG)-driven control with six-channel current stimulation in a fully wearable, non-invasive format aimed at ambulatory pain modulation. The system combines real-time sEMG acquisition, adaptive signal processing, a programmable multi-channel stimulation engine, and a high-voltage, boost-regulated power supply within a compact, battery-powered architecture. Bench-top evaluations demonstrate rapid response to EMG events and stable biphasic output (±22 mA) across all channels with high electrical isolation. A human-subject protocol using the Cold Pressor Test (CPT), heart rate variability (HRV), and galvanic skin response (GSR) has been designed to evaluate analgesic efficacy. While institutional review board (IRB) approval is pending, the system establishes a robust foundation for future personalized, mobile neuromodulation therapies. Full article

A 16-channel dual-sided flexible electrode based on a polyimide substrate was designed and fabricated using micro-electromechanical system (MEMS) technology. The electrode exhibited an average impedance of 5.9 kΩ at 1 kHz and a charge storage capacity (CSC) of 10.63 mC/cm². Concurrently, a three-dimensional finite element model incorporating electrical stimulation and micromotion-induced damage was established. The simulation results demonstrated that the implantation trauma caused by the bilateral electrode was significantly lower compared with silicon-based and cylindrical electrodes, while also enabling directional stimulation. Furthermore, leveraging the design of experiments (DOE) methodology, a multivariate regression model was developed to investigate the influence of key stimulation parameters—namely, current amplitude, frequency, and pulse width—on the volume of tissue activated (VTA). The results indicated that the regression model provided accurate predictions of VTA (R² = 0.912). Among the parameters, current amplitude and pulse width exerted a statistically significant influence on VTA size (p < 0.001), whereas the effect of frequency was comparatively minor (p = 0.387 > 0.05). This study presents the first successful fabrication and comprehensive dose–response analysis of a flexible bilateral DBS electrode. Its attributes of low implantation trauma, multi-channel capability, and directional stimulation offer a novel paradigm for precise neuromodulation. Additionally, the established stimulation parameter–VTA response model provides a robust theoretical foundation for optimizing therapeutic parameters in subsequent clinical applications. Full article

Background: Cervicogenic headache (CGH) is a prevalent secondary headache disorder associated with upper cervical spine dysfunction, often involving nociceptive convergence at the trigeminocervical complex. While manual therapy and exercise have demonstrated benefit, autonomic dysregulation may contribute to persistent symptoms. This case report explores the integration of external vagus nerve stimulation (eVNS) into a multimodal physical therapy approach targeting both mechanical and neurophysiological contributors to CGH. Case Description: A 63-year-old female presented with chronic CGH characterized by right-sided suboccipital and supraorbital pain, impaired sleep, and postural dysfunction. Examination revealed a right rotational atlas positional fault, restricted left atlantoaxial (AA) mobility, suboccipital hypertonicity, and reduced deep neck flexor endurance. Initial treatment emphasized manual therapy to restore AA mobility and atlas symmetry, combined with postural correction and neuromuscular training. Intervention: After initial symptom improvement plateaued, eVNS targeting the auricular branch of the vagus nerve was introduced to modulate autonomic tone. The patient used a handheld eVNS device nightly over three weeks. Outcomes: Substantial improvements were observed in the Neck Disability Index (↓77%), Headache Disability Inventory (↓72%), and pain scores (↓100%). Cervical mobility, atlas symmetry, and deep neck flexor endurance improved markedly. The patient reported reduced anxiety, improved sleep, and sustained headache relief at one-month follow-up. Conclusions: This case highlights the potential synergistic benefits of integrating eVNS within a physiotherapy-led CGH management plan. Further research is warranted to explore its role in targeting autonomic imbalance and enhancing conservative treatment outcomes. Full article

Background: The use of neuromodulation for the treatment of psychiatric disorders has become increasingly common, but this emerging treatment modality comes with ethical concerns. This scoping review aims to synthesize the neuroethical discourse from the past 10 years on the use of neurotechnologies for psychiatric conditions. Methods: A total of 4496 references were imported from PubMed, Embase, and Scopus. The inclusion criteria required a discussion of the neuroethics of neuromodulation and studies published between 2014 and 2024. Results: Of the 77 references, a majority discussed ethical concerns of patient autonomy and informed consent for neuromodulation, with neurotechnologies being increasingly seen as autonomy enablers. Concepts of changes in patient identity and personality, especially after deep brain stimulation, were also discussed extensively. The risks and benefits of neurotechnologies were also compared, with deep brain stimulation being seen as the riskiest but also possessing the highest efficacy. Concerns about equitable access and justice were raised regarding the rise of private transcranial magnetic stimulation clinics and the current experimental status of deep brain stimulation. Conclusions: Neuroethics discourse, particularly for deep brain stimulation, has continued to focus on how post-intervention changes in personality and behavior influence patient identity. Multiple conceptual frameworks have been proposed, though each faces critiques for addressing only parts of this complex phenomenon, prompting calls for pluralistic models. Emerging technologies, especially those involving artificial intelligence through brain computer interfaces, add new dimensions to this debate by raising concerns about neuroprivacy and legal responsibility for actions, further blurring the lines for defining personal identity. Full article